Full Text Available

Access Repository
Note: Clicking the button above will open the full text document at the original institutional repository in a new window.
Cover Image

Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children

Efavirenz and nevirapine are the most widely used agents for treatment of HIV in children. Sources of variability in their pharmacokinetics and its association with virological outcome and adverse events in African children are poorly characterised, thereby limiting treatment optimisation. To fill t...

Full description

Saved in:
Main Author: Bienczak, Andrzej Marek
Other Authors: Denti, Paolo
Format: Thesis
Language:English
Published: Division of Clinical Pharmacology 2017
Subjects:
Clinical Pharmacology
Tags: Add Tag
No Tags, Be the first to tag this record!
_version_ 1867613231872212992
access_status_str Open Access
author Bienczak, Andrzej Marek
author2 Denti, Paolo
author_browse Bienczak, Andrzej Marek
Denti, Paolo
author_facet Denti, Paolo
Bienczak, Andrzej Marek
author_sort Bienczak, Andrzej Marek
collection Thesis
description Efavirenz and nevirapine are the most widely used agents for treatment of HIV in children. Sources of variability in their pharmacokinetics and its association with virological outcome and adverse events in African children are poorly characterised, thereby limiting treatment optimisation. To fill this gap we studied population pharmacokinetics (PK) of efavirenz and nevirapine in 478 children from CHAPAS-3 (aged 0.3-1.5 years) using non-linear mixed effects modelling and identified predictors of treatment outcome and PK thresholds most predictive of increased risk of nonsuppression using Cox proportional hazards regression models and likelihood profiling. Efavirenz PK was described by 2-compartment disposition model with 1st-order elimination and transit-compartment absorption and nevirapine by 1-compartment model with elimination through a well-stirred liver model and transit-compartment absorption. Combined effect of SNPs 516GT and 983TC was the strongest predictor of between-subject variability in clearance (89% and 68% decrease between fastest/slowest CYP2B6 metabolic subgroups for efavirenz and nevirapine, respectively). PK was affected by weight, described with allometric scaling. Nevirapine intrinsic clearance displayed diurnal variations (oscillations of amplitude 29%, maximum at 12 noon), while age affected pre-hepatic bioavailability (31.7% lower at birth and increasing exponentially). In antiretroviral treatment (ART)-naïve children (n=325) increased exposures were associated with decreased risk of non-suppression for both drugs. In efavirenz, risk further increased for children>8 years and for younger boys; in nevirapine for high pre-ART VL, low pre-ART CD4% and low adherence. Thresholds most predictive of non-suppression in efavirenz were: Cmid-dose=1.12 mg/L, Cmin=0.65 mg/L and AUC0-24=28 mg∙h/L, while nevirapine had no clear threshold. Adverse events were infrequent in efavirenz, whereas in nevirapine transient transaminase elevations >grade 1 were associated with Cmin>12.4 mg/L. Non-nucleoside reverse transcriptase inhibitors dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C, in particular for efavirenz where we observe 10-fold differences in exposures between metabolic subgroups. Moreover the target Cmin and AUC0-24 could be lowered in children for efavirenz. Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
format Thesis
id oai:open.uct.ac.za:11427/25063
institution University of Cape Town (South Africa)
language eng
last_indexed 2026-06-10T12:32:51.499Z
license_str Not specified — see source repository
provenance_str_mv Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository
publishDate 2017
publishDateRange 2017
publishDateSort 2017
publisher Division of Clinical Pharmacology
publisherStr Division of Clinical Pharmacology
record_format dspace
source_str UCTD — University of Cape Town Open Access Repository
spelling oai:open.uct.ac.za:11427/25063 Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children Bienczak, Andrzej Marek Denti, Paolo McIlleron, Helen Clinical Pharmacology Efavirenz and nevirapine are the most widely used agents for treatment of HIV in children. Sources of variability in their pharmacokinetics and its association with virological outcome and adverse events in African children are poorly characterised, thereby limiting treatment optimisation. To fill this gap we studied population pharmacokinetics (PK) of efavirenz and nevirapine in 478 children from CHAPAS-3 (aged 0.3-1.5 years) using non-linear mixed effects modelling and identified predictors of treatment outcome and PK thresholds most predictive of increased risk of nonsuppression using Cox proportional hazards regression models and likelihood profiling. Efavirenz PK was described by 2-compartment disposition model with 1st-order elimination and transit-compartment absorption and nevirapine by 1-compartment model with elimination through a well-stirred liver model and transit-compartment absorption. Combined effect of SNPs 516GT and 983TC was the strongest predictor of between-subject variability in clearance (89% and 68% decrease between fastest/slowest CYP2B6 metabolic subgroups for efavirenz and nevirapine, respectively). PK was affected by weight, described with allometric scaling. Nevirapine intrinsic clearance displayed diurnal variations (oscillations of amplitude 29%, maximum at 12 noon), while age affected pre-hepatic bioavailability (31.7% lower at birth and increasing exponentially). In antiretroviral treatment (ART)-naïve children (n=325) increased exposures were associated with decreased risk of non-suppression for both drugs. In efavirenz, risk further increased for children>8 years and for younger boys; in nevirapine for high pre-ART VL, low pre-ART CD4% and low adherence. Thresholds most predictive of non-suppression in efavirenz were: Cmid-dose=1.12 mg/L, Cmin=0.65 mg/L and AUC0-24=28 mg∙h/L, while nevirapine had no clear threshold. Adverse events were infrequent in efavirenz, whereas in nevirapine transient transaminase elevations >grade 1 were associated with Cmin>12.4 mg/L. Non-nucleoside reverse transcriptase inhibitors dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C, in particular for efavirenz where we observe 10-fold differences in exposures between metabolic subgroups. Moreover the target Cmin and AUC0-24 could be lowered in children for efavirenz. Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity. 2017-09-06T07:06:12Z 2017-09-06T07:06:12Z 2017 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/25063 eng application/pdf Division of Clinical Pharmacology Faculty of Health Sciences University of Cape Town
spellingShingle Clinical Pharmacology
Bienczak, Andrzej Marek
Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
thesis_degree_str Doctoral
title Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
title_full Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
title_fullStr Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
title_full_unstemmed Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
title_short Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
title_sort pharmacokinetics pharmacogenetics and optimisation of treatment with non nucleoside reverse transcriptase inhibitors in hiv infected african children
topic Clinical Pharmacology
url http://hdl.handle.net/11427/25063
work_keys_str_mv AT bienczakandrzejmarek pharmacokineticspharmacogeneticsandoptimisationoftreatmentwithnonnucleosidereversetranscriptaseinhibitorsinhivinfectedafricanchildren

Similar Items